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WO2019235577A1 - Agent prophylactique ou thérapeutique contre une maladie induite par le stress oxydatif - Google Patents

Agent prophylactique ou thérapeutique contre une maladie induite par le stress oxydatif Download PDF

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Publication number
WO2019235577A1
WO2019235577A1 PCT/JP2019/022558 JP2019022558W WO2019235577A1 WO 2019235577 A1 WO2019235577 A1 WO 2019235577A1 JP 2019022558 W JP2019022558 W JP 2019022558W WO 2019235577 A1 WO2019235577 A1 WO 2019235577A1
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Prior art keywords
therapeutic agent
preventive
agent according
silicon
fine particles
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PCT/JP2019/022558
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English (en)
Japanese (ja)
Inventor
昌一 島田
佳久 小山
近藤　誠
紀好 臼井
和也 大畠
秀典 猪原
小林　光
悠輝 小林
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国立大学法人大阪大学
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Priority to CN201980038513.2A priority Critical patent/CN112351783A/zh
Priority to CN202310641540.7A priority patent/CN117860776A/zh
Priority to EP19815281.1A priority patent/EP3804732B1/fr
Priority to JP2019204864A priority patent/JP7461003B2/ja
Priority to JP2019210724A priority patent/JP7461004B2/ja
Priority to JP2019212972A priority patent/JP7461006B2/ja
Priority to JP2019212974A priority patent/JP7461008B2/ja
Priority to JP2019213067A priority patent/JP7461011B2/ja
Priority to JP2019212971A priority patent/JP7461005B2/ja
Priority to JP2019213066A priority patent/JP7461010B2/ja
Priority to JP2019212973A priority patent/JP7461007B2/ja
Priority to JP2019213065A priority patent/JP7461009B2/ja
Publication of WO2019235577A1 publication Critical patent/WO2019235577A1/fr
Priority to US17/113,886 priority patent/US20210145865A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction

Definitions

  • the present invention relates to prevention or treatment of diseases caused by oxidative stress.
  • Active oxygen is necessary for life support, it is known to oxidize and damage cells constituting the living body.
  • Active oxygen includes superoxide anion radical, hydroxyl radical, hydrogen peroxide, and singlet oxygen.
  • Hydroxyl radical is a radical having a very high oxidizing power, and when it is generated in a living body, for example, DNA, lipid, It is known to oxidize proteins and damage organs. The hydroxyl radical is considered to cause various diseases such as cancer and lifestyle-related diseases and aging by such an action. It has been reported that even in the large intestine, damage is induced due to oxidation by hydroxy radicals and inflammation is increased (Non-patent Document 1).
  • Hydrogen is known as a substance that extinguishes hydroxyl radicals generated in the body. Hydrogen is produced by reaction with hydroxyl radicals, and does not produce substances that are harmful to the body. Therefore, there are many reports on hydrogen water containing hydrogen that extinguishes hydroxyl radicals in the body.
  • the saturated hydrogen concentration is 1.6 ppm at room temperature, and the amount of hydrogen contained in 1 liter of hydrogen water is only 18 ml (milliliter) in terms of gas even in a saturated state.
  • hydrogen in hydrogen water passes through the container and diffuses into the air, and it is difficult to maintain the amount of dissolved hydrogen in the hydrogen water.
  • burp anaerobic symptoms
  • Silicon (silicon, Si) is used in a wide range of fields such as semiconductor materials.
  • the inventors of the present application have studied various reactivity of silicon fine particles with water.
  • silicon fine particles can be in contact with water to generate hydrogen.
  • the reaction is shown by the following formula. Si + 2H 2 O ⁇ SiO 2 + 2H 2 Further, it was found that this reaction hardly progressed when contacted with water having a pH of less than 5, and the reaction proceeded when contacted with water having a pH of 7 or higher, and that the reaction proceeded faster at pH8 or higher. Moreover, it discovered that the said reaction progressed suitably by surface-treating silicon microparticles. Further, while the silicon fine particles were in contact with water, hydrogen was continuously generated over 20 hours or more, and depending on the conditions, it was found that 400 g or more of hydrogen was generated from 1 g of silicon fine particles (Patent Documents 1 to 6). Non-Patent Document 2). 400 ml of hydrogen corresponds to hydrogen contained in 22 liters of saturated hydrogen water.
  • Inflammatory diseases are diseases accompanied by inflammatory symptoms. Inflammation includes inflammation that develops systemically and inflammation that develops locally. Examples of systemic inflammation include sepsis and the like, and examples of local inflammation include inflammatory bowel disease and arthritis.
  • IBD inflammatory bowel disease
  • ulcerative colitis and Crohn's disease which are nationally designated intractable diseases
  • complete cure is difficult because no radical therapy has been established .
  • the current treatment is symptomatic therapy, and the main symptomatic therapy is the drug therapy listed below.
  • Anti-inflammatory agent 5-aminosalicylic acid agent
  • corticosteroid agent anti-cytokine therapy: anti-TNF ⁇ antibody preparation
  • Immunosuppressant Azathioprine, 6-MP (mercaptopurine)
  • LCAP leukocyte ablation therapy
  • GCAP granulocyte ablation therapy
  • surgical treatment ulcerative colitis: creation of colostomy, Crohn's disease: resection of small area And stenosis formation.
  • Arthritis is mainly caused by joint swelling and pain, with suppuration and pain, and may exhibit movement disorders. It can be broadly divided into bacterial substances such as tuberculosis and syphilis and those caused by rheumatism and trauma. Since the number of affected patients increases year by year due to the aging of the population and the increase in obesity, and the economic burden will become enormous in several years, the development of more effective therapeutic and preventive drugs is urgent. Current therapies include conservative treatments and surgical treatments.
  • the former includes rehabilitation-centered exercise therapy, hyperthermia to reduce pain, orthodontic therapy using auxiliaries such as walking sticks, and pharmacotherapy (anti-inflammatory analgesics: NSAIDs, antirheumatic drugs: DMARDs, steroids, JAK inhibitors, hyaluronic acid preparations and so on.
  • NSAIDs anti-inflammatory analgesics
  • DMARDs antirheumatic drugs
  • steroids JAK inhibitors
  • hyaluronic acid preparations and so on.
  • the latter includes arthroscopic surgery, high tibial osteotomy, and knee replacement.
  • Anticancer drug treatment is one of the useful cancer treatments such as cancer growth suppression and tumor shrinkage, but nausea / vomiting, diarrhea and anemia may occur. In particular, nausea and vomiting significantly reduce the patient's quality of life, and its control is very important.
  • the vomiting reflex occurs through serotonin and substance P, with anticancer agents stimulating the small intestine and the dorsal medullary vomiting center.
  • the frequency of vomiting varies depending on the type of anticancer drug, and cisplatin and the like are classified as highly emetic risk (emetic frequency of 90% or more).
  • Therapeutic agents include serotonin 3 receptor antagonists (ondansetron, palonosetron, etc.), dopamine D2 receptor antagonists (donveridone, etc.), steroids (dexamethasone, etc.), NK1 receptor antagonists (aprepitant, fosaprepitant, etc.), etc. Antiemetics.
  • Symptoms of depression include depression, sleep disorders, loss of interest / joy, loss of appetite, reduced thinking / concentration / decision, valuelessness / self-responsibility, fatigue, and decreased spirit.
  • the number of patients is increasing.
  • Treatment for depression is a pharmacotherapy centered on selective serotonin reuptake inhibitors (SSRI), but the remission rate remains below 50%, so the development of new therapies is desired. Yes.
  • SSRI selective serotonin reuptake inhibitors
  • Parkinson's disease develops due to a decrease in substantia nigra dopamine neurons and is characterized by progressive motor dysfunction (muscular rigidity, slow movement, postural disability) and uncontrollable tremor (tremor). It is said. It is designated as a designated intractable disease in Japan. Current treatment is mainly symptomatic and there is no radical cure.
  • As drug therapy L-DOPA preparations, dopamine agonists, anticholinergic drugs, amantadine hydrochloride, levodopa combination drugs, adrenergic receptor stimulants, and the like are used. If the symptoms are not improved by drug therapy, surgical treatment by stereotaxic surgery such as coagulation and deep brain stimulation is being performed.
  • Autism spectrum disorder is a developmental disorder that shows social communication disorder, limited / repeated behavior / interest, hypersensitivity and dullness, and the prevalence in Japan is estimated to be about 1-3%.
  • DSM-5 diagnostic criteria introduced by the American Psychiatric Association since 2013 include autism (autistic disorder), Asperger's syndrome, childhood disintegrative disorder, unspecified diffuse developmental disorder It is included. There is no fundamental cure for autism spectrum disease, only symptomatic treatment.
  • the main therapies are 1) psychostimulants, 2) antipsychotics, 3) atypical antipsychotics, 4) antidepressants, 5) anxiolytics, 6) epilepsy drugs, 7) antihistamines, 8 ) Cardiovascular drugs, 9) Others (cholinesterase inhibitors, etc.) are used.
  • education after diagnosis and guidance on how to raise a family are the current effective treatments.
  • Memory impairment is a disorder that forgets what you have experienced and past memories, and is one of the core symptoms of dementia. From mild cognitive impairment to dementia, the treatment for memory impairment is mainly symptomatic and there is no radical cure. As the symptomatic treatment, donepezil hydrochloride, galantamine hydrobromide, rivastigmine, and the like have been developed, but sufficient effects have not been obtained.
  • Cervical spine injury accounts for 70%, and many of the patients are elderly, and the cause is many falls and falls. About 5,000 people are injured annually, and the total number of patients is over 100,000 to 200,000 due to intractability. With current medical care, it is impossible to restore the damaged spinal cord itself, and even after treatment, functional improvement is not sufficient.
  • the steroid succinic acid methylprednisolone sodium ester is the only approved treatment, but it is currently being used because of the high incidence of respiratory and gastrointestinal side effects. Rehabilitation is effective for functional recovery, but prognosis is greatly affected by acute inflammation. Therefore, the development of therapeutic agents for acute inflammation is urgent.
  • Listening inconvenience occurs in 1 out of 10 people in Japan, and there are various causes such as noise, cerebral infarction, viral infection, aging and side effects of medication. Improving hearing loss, which significantly degrades quality of life (QOL), is urgent, but current treatment is symptomatic and difficult to cure.
  • the main symptomatic treatment is mainly suppression of inflammation and abnormal immunity by steroid drugs. It is usually administered by drinking or infusion, but if there is no effect, it may be injected into the tympanic chamber.
  • Diabetes is a disease in which hyperglycemia continues chronically due to decreased or insufficient insulin action.
  • Risk factors for onset include aging, family history, obesity, lack of exercise, and impaired glucose tolerance. Without any subjective symptoms, it may be accompanied by serious complications of retinopathy, nephropathy and neuropathy, and it is a very dangerous disease.
  • Early treatment and prevention of onset are very important. Glycemic control is important for the treatment of diabetes. First, diet therapy and exercise therapy are performed.
  • Oral hypoglycemic drug insulin resistance improving system (biguanide drug, thiazolidine drug); insulin secretion promoting system (SU drug, glinide drug, DPP-4 inhibitor)); sugar absorption ⁇ Drug therapy using an excretion regulating system ( ⁇ -Gl inhibitor, SLGT2 inhibitor, etc.) is performed.
  • Hangover caused by alcohol consumption presents various symptoms such as headache, sleep disturbance, nausea, vomiting, cognitive and sensory disturbances, depression, and autonomic symptoms.
  • the onset of hangover involves factors such as oxidative stress, mild withdrawal symptoms of alcohol, acidity of body fluids, increased inflammatory response, gastrointestinal disorders, changes in hormone secretion (diuresis, dehydration, hypoglycemia), acetaldehyde, etc.
  • Symptomatic treatment includes drip administration of glucose solution and oral administration of gastrointestinal drugs.
  • there are many food candidates that speed up recovery but only those ingredients that contain ⁇ -linolenic acid (quail eggs, green fish, etc.) have scientific basis.
  • An object of the present invention is to provide a medicine, a medical device, a sanitary product, a food, a beverage, or the like for prevention or treatment of a disease caused by oxidative stress.
  • silicon fine particles can prevent and / or treat diseases caused by oxidative stress, and have completed the present invention.
  • a preventive or therapeutic agent for diseases caused by oxidative stress excluding kidney diseases
  • the preventive or therapeutic agent according to item 1 wherein the disease caused by oxidative stress is an inflammatory disease.
  • 3. The preventive or therapeutic agent according to item 2 above, wherein the inflammatory disease is an inflammatory disease of the digestive tract. 4).
  • 4. The preventive or therapeutic agent according to item 3 above, wherein the inflammatory disease of the digestive tract is an inflammatory bowel disease. 5).
  • the preventive or therapeutic agent according to 5 above, wherein the arthritis is rheumatoid arthritis. 7). 3. The preventive or therapeutic agent according to item 2 above, wherein the inflammatory disease is hepatitis. 8). 8. The preventive or therapeutic agent according to item 7 above, wherein the hepatitis is acute hepatitis. 9. 3. The preventive or therapeutic agent according to item 2 above, wherein the inflammatory disease is dermatitis. 10. 10. The preventive or therapeutic agent according to 9 above, wherein the dermatitis is contact dermatitis. 11. 2. The preventive or therapeutic agent according to item 1, wherein the disease caused by oxidative stress is visceral discomfort. 12 12.
  • the preventive or therapeutic agent according to 11 above, wherein the visceral discomfort is at least one selected from the group consisting of visceral pain, vomiting, nausea, belly and diarrhea. 13. 12. The preventive or therapeutic agent according to 11 above, wherein the visceral discomfort is visceral pain associated with inflammatory bowel disease. 14 12. The preventive or therapeutic agent according to 11 above, wherein the visceral discomfort is visceral discomfort associated with administration of an anticancer agent. 15. 15. The preventive or therapeutic agent according to 14 above, wherein the visceral discomfort associated with administration of the anticancer agent is nausea or vomiting associated with administration of the anticancer agent. 16. 2. The preventive or therapeutic agent according to item 1 above, wherein the disease caused by oxidative stress is depression or depression. 17. 2.
  • the preventive or therapeutic agent according to item 1 above, wherein the disease caused by oxidative stress is Parkinson's disease. 18. 2. The preventive or therapeutic agent according to 1 above, wherein the disease caused by oxidative stress is autism spectrum disease. 19. 19. The preventive or therapeutic agent according to item 18 above, wherein the autism spectrum disorder is a social communication disorder. 20. 2. The preventive or therapeutic agent according to item 1, wherein the disease caused by oxidative stress is memory impairment. 21. 2. The preventive or therapeutic agent according to item 1, wherein the disease caused by oxidative stress is spinal cord injury. 22. 22. The preventive or therapeutic agent according to item 21 above, wherein the spinal cord injury is a motor dysfunction associated with spinal cord injury. 23. 2.
  • the preventive or therapeutic agent according to item 1 above, wherein the disease caused by oxidative stress is deafness. 24. 24. The preventive or therapeutic agent according to 23 above, wherein the hearing loss is noise-induced hearing loss. 25. 2. The preventive or therapeutic agent according to item 1 above, wherein the disease caused by oxidative stress is cerebral ischemia injury or reperfusion injury after cerebral ischemia. 26. 2. The preventive or therapeutic agent according to item 1 above, wherein the disease caused by oxidative stress is diabetes. 27. 27. The preventive or therapeutic agent according to item 26, wherein the diabetes is type 2 diabetes. 28. 2. The preventive or therapeutic agent according to item 1, wherein the disease caused by oxidative stress is hangover. 29. 29.
  • the preventive or therapeutic agent according to any one of 1 to 37 above which is for oral administration.
  • a medical device comprising the prophylactic or therapeutic agent according to any one of items 1 to 38.
  • a sanitary article comprising the preventive or therapeutic agent according to any one of items 1 to 38.
  • a food or beverage containing the preventive or therapeutic agent according to any one of 1 to 38 above.
  • a method for treating a disease caused by oxidative stress which comprises administering a drug containing silicon fine particles.
  • the preventive or therapeutic agent of the present invention can prevent and / or treat diseases caused by oxidative stress. Its preventive and therapeutic effects are very good.
  • the silicon fine particles contained in the preventive or therapeutic agent of the present invention are fine particles capable of generating hydrogen. Since OH ⁇ ions act catalytically in the hydrogen generation reaction, hydrogen efficiently generates hydrogen for 20 hours or more under alkaline conditions. On the other hand, the residence time of food in the human intestine is usually 20 hours or more.
  • the prophylactic or therapeutic agent of the present invention administered orally can continue to generate hydrogen over a long period of time in the intestine and continue to distribute hydrogen in the body. Further, when the preventive or therapeutic agent of the present invention is placed on the skin or mucous membrane for a long time, it is considered that hydrogen can be continuously delivered into the body for a long time. By continuing to distribute hydrogen in this way, it is considered that the antioxidant power in the body is improved and the improved antioxidant power is maintained.
  • the preventive or therapeutic agent of the present invention exhibits a remarkably superior effect as compared with hydrogen water. Hydrogen water or gaseous hydrogen could not continue to deliver hydrogen continuously in the body for a long time, but the preventive or therapeutic agent of the present invention continuously delivers hydrogen to the body for a long time. Can do. Furthermore, since the prophylactic or therapeutic agent of the present invention has a remarkable effect, it is also considered that it has an action not found in hydrogen water.
  • Prevention and treatment with the preventive or therapeutic agent of the present invention can be one of the causal therapies for diseases caused by oxidative stress.
  • Causal therapy is both effective and safe.
  • the preventive or therapeutic agent of the present invention is excellent in safety because the product produced by reaction with hydroxyl radical is water.
  • the number of patients with diseases caused by oxidative stress has increased in recent years, and there are many diseases for which there is no radical treatment, and finding causal therapies for diseases caused by oxidative stress greatly contributes to future medical care and health promotion. To do.
  • the preventive or therapeutic agent of the present invention does not diffuse hydrogen prior to administration like hydrogen water. This property contributes to product quality maintenance and to the convenience of manufacturers, sellers and users.
  • FIG. 1 is a graph showing the amount of hydrogen (cumulative amount) per gram of silicon fine particles generated by bringing the silicon fine particles obtained in Example 2 into contact with water at 36 ° C. and pH 8.2.
  • FIG. 2 is a photograph of an aggregate of silicon crystallites taken with a scanning electron microscope (SEM).
  • FIG. 3 is a graph showing the results of the antioxidant power (BAP test) of plasma of normal SD rats administered with silicon microparticles for 8 weeks.
  • Con represents a control group
  • Si represents a silicon fine particle administration group.
  • FIG. 4 is a graph showing the results of administration of silicon microparticles to mice in which inflammation was induced by lipopolysaccharide (LPS).
  • Con represents a control group
  • Si represents a silicon fine particle administration group.
  • FIG. 5 is a graph showing the concentrations of two lipid peroxides, LPO (Lipid hydroperoxide) and HEL (hexanoyllysine) in blood after administration of silicon microparticles to an inflammatory bowel disease model mouse.
  • Con represents a control group
  • Si represents a silicon fine particle administration group.
  • FIG. 6 is a graph showing the results (weight loss rate, colitis score, and survival rate) of silicon fine particles administered to inflammatory bowel disease model mice.
  • FIG. 7 is a photograph showing the state of the large intestine after administration of silicon microparticles to an inflammatory bowel disease model mouse and a graph showing the length (cm) of the large intestine.
  • Con represents a control group
  • Si represents a silicon fine particle administration group.
  • FIG. 8 is a photograph showing the state of the large intestine after administration of silicon microparticles to wild-type mice (sham) and inflammatory bowel disease model mice, and a graph showing the length (cm) of the large intestine.
  • Con represents a control group
  • Si represents a silicon fine particle administration group.
  • FIG. 9 shows histopathological images of the colon and rectum on the third day (3d) from the start of DSS (dextran sulfate sodium) administration.
  • Si represents a silicon fine particle administration group.
  • FIG. 10 shows the histopathological images of the colon and rectum on the fifth day (5d) from the start of DSS administration.
  • Si represents a silicon fine particle administration group.
  • FIG. 11 shows the result of analyzing the degree of crypt collapse. Con represents a control group, and Si represents a silicon fine particle administration group.
  • FIG. 12 shows a fluorescent immunostaining photograph of the medullary dorsal region, which is the central region of vomiting. The white signal indicates c-Fos positive cells that are neuronal activity marker factors.
  • Con is the medullary dorsal side of the control model mouse
  • Si is the medullary dorsal side of the model mouse administered with the silicon microparticles.
  • AP is the last area
  • cc is the central canal
  • 12N is the hypoglossal nucleus. Circles indicate the location of the vagus nerve dorsal motor nucleus and solitary nucleus responding to visceral discomfort and visceral pain.
  • the green fluorescence signal is shown by the white signal.
  • FIG. 13 shows a fluorescent immunostaining photograph of the amygdala. The white signal indicates c-Fos positive cells that are neuronal activity marker factors.
  • Con is the amygdala of a control model mouse
  • Si is the amygdala of a model mouse to which silicon fine particles are administered.
  • the upper two upper and lower sheets are the left amygdala of the same mouse, and the lower is the right amygdala.
  • BLA indicates the amygdala basolateral nucleus.
  • the arrow points to the central nucleus of the amygdala that reacts to pain such as visceral pain.
  • the green fluorescence signal is shown by the white signal.
  • FIG. 14 is a graph showing the dissolved hydrogen concentration of hydrogen water produced for comparison.
  • FIG. 15 is a graph showing a pathological image showing the state of the large intestine after administration of silicon microparticles or hydrogen water to an inflammatory bowel disease model mouse and the degree of shortening of the large intestine.
  • Con represents a control group
  • Si represents a silicon fine particle administration group
  • Hydrogen Water represents a hydrogen water administration group.
  • FIG. 16 is a graph showing the incidence of arthritis in the normal diet group and the silicon microparticle-containing diet group in arthritis model mice. The vertical axis shows the incidence of arthritis.
  • FIG. 17 is a graph showing the “arthritic index (average of all limbs)” of the normal diet group and the silicon fine particle-containing diet group in arthritis model mice.
  • Each limb based on arthritis criteria (4 grades; 0: no change; 1: swelling of the toes; 2: swelling of the toes and soles, instep; 3: swelling of the entire foot; 4: severe swelling)
  • the degree of inflammation is scored and used as the arthritis index
  • the average value of the arthritis index of each limb (limb) is the arthritis index of each individual (average of all limbs)
  • the average value of the arthritic index (average of all limbs) of each individual in each group This is shown in FIG.
  • FIG. 18 is a graph showing the “arthritic index (maximum inflamed limb)” of the normal diet group and the silicon fine particle-containing diet group in arthritis model mice.
  • Maximum inflammation based on arthritis criteria (4 grades; 0: no change; 1: swelling of the toes; 2: swelling of the toes and soles, instep; 3: swelling of the entire foot; 4: severe swelling)
  • the degree of inflammation of the limbs was scored and used as the arthritis index (maximum inflammatory limb) of each individual.
  • FIG. 19 is a graph showing the thickness of the pinna of contact dermatitis model mice. The first day shows the actual thickness (mm) of the auricle before sensitization, the second day after one day of the sensitization day, and the third day after two days after the sensitization day. Si represents a silicon fine particle administration group, and Con represents a control group.
  • FIG. 20 shows the degree of thickening in the contact dermatitis model mice (difference in ear thickness on day 1 and day 2, difference in ear thickness on day 2 and day 3, day 1 and day 3) It is a graph which shows the difference of auricle thickness.
  • Si represents a silicon fine particle administration group, and Con represents a control group.
  • FIG. 21 is a graph showing the survival rate of acute hepatitis model mice.
  • Si represents a silicon fine particle administration group, and Con represents a control group.
  • the left figure is a comparison of the average values of the survival rates of the respective groups, and the right figure is a graph comparing the individual survival rates.
  • FIG. 22 is a photograph showing the results of fluorescent immunostaining of the vomiting center on the dorsal side of the medulla of the anti-cancer drug-taking model mouse.
  • the red fluorescent signal indicates c-Fos positive cells, a neuronal activity marker.
  • the photo in the drawing is grayscale and the tone is reversed so that the signal is easy to see, and the red signal is shown as a black dot.
  • (A) is an anticancer drug-taking model mouse fed with a normal food
  • (b) is an anticancer drug-taking model mouse fed with a silicon fine particle-containing food.
  • FIG. 23 is a graph showing the results of counting the number of positive cells in a c-Fos immunostaining result photograph of the emetic center on the dorsal medulla dorsal side of a model mouse taking an anticancer drug.
  • the vertical axis represents the number of c-Fos positive cells.
  • FIG. 24 is a graph showing immobility time (seconds) in the tail suspension test of depression model mice (LPS) and normal mice (Sal). (1) indicates a silicon fine particle administration group, and ( ⁇ ) indicates a control group.
  • FIG. 25 is a graph showing immobility time (seconds) in a forced swimming test of a depression model mouse (LPS) and a normal mouse (Sal).
  • FIG. 26 is a graph showing the amount of spontaneous activity in depression model mice (LPS) and normal mice (Sal). (1) indicates a silicon fine particle administration group, and ( ⁇ ) indicates a control group.
  • the depression model mice (LPS) and normal mice (Sal) subjected to the tail suspension test and the forced swimming test show that there is no difference in the amount of spontaneous activity regardless of the presence or absence of silicon fine particle administration.
  • FIG. 27 is a coronal cross-section of the forebrain including the mouse striatum, and is an image showing a site where 6-hydroxydopamine hydrochloride (6-OHDA) is injected to produce a Parkinson's disease model mouse.
  • 6-OHDA 6-hydroxydopamine hydrochloride
  • FIG. 28 is a graph showing the results of a rotational movement test by administration of apomorphine in Parkinson's disease model mice and normal mice.
  • the vertical axis represents the rotation speed.
  • Control represents a normal diet group of normal mice
  • Control + Si represents a dietary group containing silicon fine particles of normal mice
  • 6-OHDA represents a normal diet group of Parkinson's disease model mice
  • 6-OHDA + Si represents a dietary group containing silicon fine particles of Parkinson's disease model mice.
  • FIG. 29 is an immunohistochemically-stained image of a coronal section of the forebrain of a Parkinson's disease model mouse.
  • Dopamine synthase (tyrosine water) present at the dopaminergic cell axon terminal of the substantia nigra projected into the striatum. It is a dyeing
  • 6-OHDA represents a Parkinson's disease model mouse with a normal diet
  • 6-OHDA + Si represents a Parkinson's disease model mouse with a diet containing silicon fine particles. Each image is an image of another individual.
  • FIG. 30 is an immunohistochemically-stained image of a coronal section of the midbrain of a Parkinson's disease model mouse, a stained image of dopamine synthase (tyrosine hydroxylase) present in the cell body of dopaminergic cells present in the substantia nigra. is there.
  • 6-OHDA represents a Parkinson's disease model mouse with a normal diet
  • 6-OHDA + Si represents a Parkinson's disease model mouse with a diet containing silicon fine particles.
  • Each image is an image of another individual. Arrows indicate dopaminergic neurons that have been shed by 6-OHDA administration.
  • FIG. 31 is a graph showing rotarod residence times of Parkinson's disease model mice and normal mice. The vertical axis represents the stay time (seconds).
  • Control is a normal diet group of normal mice
  • Control + Si is a dietary group containing silicon fine particles of normal mice
  • 6-OHDA is a normal diet group of Parkinson's disease model mice
  • 6-OHDA + Si is a dietary group containing silicon fine particles of Parkinson's disease mouse models.
  • FIG. 32 shows the results of spontaneous activity measurement (Supermex) and open field test in Parkinson's disease model mice and normal mice.
  • A) is the spontaneous activity
  • (b) is the open field test travel distance
  • (c) is the open field test travel speed
  • (d) is the open field test activity time / immobility. Time (left in each group is activity time, right is immobility time), and the vertical axis indicates time (seconds).
  • Control is a normal diet group of normal mice
  • Control + Si is a dietary group containing silicon fine particles of normal mice
  • 6-OHDA is a normal diet group of Parkinson's disease model mice
  • 6-OHDA + Si is a dietary group containing silicon fine particles of Parkinson's disease model mice Indicates.
  • FIG. 33 is a graph showing the results of an ultrasonic vocal communication test between mother and child.
  • FIG. 34 is a graph showing the freezing time (%) in the context-conditioned fear memory test.
  • FIG. 35 is a graph showing the amount of self-activity.
  • FIG. 36 is a graph showing the motor function of the normal food group and the silicon fine particle-containing food group in the spinal cord injury model mouse as a BBB score average value. The horizontal axis shows the week after surgery.
  • ⁇ Normal food group, ⁇ : Silicon fine particle-containing food group; ** p ⁇ 0.05, * p ⁇ 0.01 (t test)
  • FIG. 37 is a graph showing BBB scores of individual spinal cord injury model mice one week after the operation.
  • FIG. 38 is a graph showing the hearing ability of the normal food group and the silicon fine particle-containing food group in the deafness model mouse.
  • the vertical axis represents the auditory threshold (db), and the horizontal axis represents the frequency (kHz).
  • FIG. 39 is a graph showing the results of observing neurological symptoms during 90 minutes of ischemia in cerebral ischemia / reperfusion injury model rats. Each rat was evaluated on a scale of 0 to 3 for each item. Severe neurological symptoms are high. ( ⁇ indicates a silicon fine particle administration group, and ⁇ indicates a control group.
  • FIG. 40 is a graph showing the survival rate after 3 days of cerebral ischemia / reperfusion surgery in cerebral ischemia / reperfusion injury model rats. (1) indicates a silicon fine particle administration group, and ( ⁇ ) indicates a control group.
  • FIG. 40 is a graph showing the survival rate after 3 days of cerebral ischemia / reperfusion surgery in cerebral ischemia / reperfusion injury model rats. (1) indicates a silicon fine particle administration group, and ( ⁇ ) indicates a control group.
  • FIG. 41 is a graph showing the results of behavioral evaluation (Elevated Body Swing test (modified)) performed 3 days after cerebral ischemia / reperfusion surgery in cerebral ischemia / reperfusion injury model rats. The presence or absence of a twist (swing) of the body of a mouse hung upside down with a tail is observed, and the ratio of the swinged individuals among all the evaluated individuals is shown in the graph. (1) indicates a silicon fine particle administration group, and ( ⁇ ) indicates a control group.
  • FIG. 42 is a graph showing measured body weight values (g) of a normal diet group and a silicon microparticle-containing diet group in a diabetes model mouse. The vertical axis represents body weight (g), and the horizontal axis represents time (weeks).
  • FIG. 43 is a graph showing blood test results and urine test results of a diabetes model mouse fed with a normal diet and a diabetes model mouse fed with a diet containing silicon fine particles. In order from the left, blood glucose level (mg / dL), neutral fat mass (mg / dL), total ketone body mass ( ⁇ mol / L) and urine sugar level (mg / dL) are shown.
  • ⁇ Normal diet diabetes model mouse
  • ⁇ Silicon microparticle-containing diet diabetes model mouse
  • FIG. 44 is a graph showing the amount of spontaneous activity of the hangover mouse model.
  • FIG. 45 is a graph showing the rotarod stay time of the hangover mouse model.
  • (1) indicates a silicon fine particle administration group, and ( ⁇ ) indicates a control group.
  • FIG. 46 shows the results of an open field test of a hangover mouse model.
  • A) is a graph which shows a movement distance.
  • B) is a graph which shows a moving speed.
  • C is a graph showing active time and immobility time.
  • (1) indicates a silicon fine particle administration group, and ( ⁇ ) indicates a control group.
  • the silicon fine particles contained in the preventive or therapeutic agent of the present invention may be fine particles containing silicon that can generate hydrogen in contact with water.
  • silicon fine particles containing silicon that can generate hydrogen in contact with water (silicon fine particles having hydrogen generating ability) generate hydrogen continuously when in contact with water at 36 ° C. and pH 8.2. It means silicon fine particles capable of generating 10 ml or more of hydrogen per gram of silicon fine particles in 24 hours. Preferably, they are 20 ml or more, 40 ml or more, 80 ml or more, 150 ml or more, 200 ml or more, 300 ml or more.
  • the silicon fine particles contained in the preventive or therapeutic agent of the present invention are preferably silicon fine particles, aggregates of the silicon fine particles, and / or porous silicon particles (porous silicon particles).
  • the active ingredient of the preventive or therapeutic agent of the present invention is preferably at least one kind of particles selected from the group consisting of silicon fine particles, aggregates of the silicon fine particles, and porous silicon particles. That is, the preferred active ingredient may be silicon fine particles alone, an aggregate of silicon fine particles alone, or porous silicon particles alone. Further, two or more kinds of silicon fine particles may be contained as an active ingredient.
  • the prophylactic or therapeutic agent of the present invention preferably contains silicon fine particles and / or aggregates of the silicon fine particles. More preferably, the main component is an aggregate of fine silicon particles.
  • the silicon fine particles in the present invention are preferably fine particles made of silicon alone. However, when silicon simple particles are exposed to the atmosphere, the surface is oxidized to form a silicon oxide film. Therefore, the silicon fine particles in the present invention are preferably fine particles having a silicon oxide film formed on the surface.
  • Preferred silicon fine particles in the present invention are fine particles made of silicon alone, silicon fine particles having a silicon oxide film formed on the surface thereof, aggregates of the silicon fine particles, and particles made of porous silicon alone. And at least one particle selected from the group consisting of porous silicon particles having a silicon oxide film formed on the surface thereof.
  • the silicon content in the silicon fine particles is preferably 10% by weight or more, more preferably 20% by weight or more, further preferably 50% by weight or more, and most preferably 70% by weight or more.
  • the silicon simple substance is high purity silicon.
  • high-purity silicon is silicon having a purity of silicon of 99% or higher, preferably 99.9% or higher, more preferably 99.99% or higher.
  • silicon particles There is no limitation on the shape of silicon particles. Examples include indeterminate shapes, polygons, spheres, ellipses, and cylinders.
  • the silicon fine particles may be crystalline silicon fine particles having crystallinity. Further, it may be amorphous silicon fine particles having no crystallinity. If it has crystallinity, it may be single crystal or polycrystal. Crystal silicon fine particles are preferable, and single crystal silicon fine particles are more preferable.
  • the amorphous silicon fine particles may be amorphous silicon fine particles formed by a plasma CV method, a laser ablation method, or the like.
  • the silicon oxide film formed on the surface of the silicon fine particles in the present invention may be a silicon oxide film formed by being exposed to the atmosphere and being naturally oxidized. Further, it may be a silicon oxide film artificially formed by a known method such as chemical oxidation with an oxidizing agent such as nitric acid.
  • the thickness of the silicon oxide film may be a thickness that allows fine particles made of silicon alone to be stable and to efficiently generate hydrogen. For example, they are 0.3 nm to 3 nm, 0.5 nm to 2.5 nm, 0.7 to 2 nm, 0.8 nm to 1.8 nm, 1.0 to 1.7 nm.
  • the silicon oxide film is a film containing oxides such as Si 2 O, SiO, Si 2 O 3 , and SiO 2 in which silicon on the surface of fine particles made of silicon alone is combined with oxygen. Si 2 O, SiO, Si 2 O 3 and the like promote the hydrogen generation reaction.
  • the silicon fine particles may be crystalline silicon fine particles having crystallinity. Further, it may be amorphous silicon fine particles having no crystallinity. If it has crystallinity, it may be single crystal or polycrystal.
  • Preferred silicon fine particles are crystalline silicon fine particles, and more preferably single crystal silicon fine particles (hereinafter also referred to as silicon crystallites).
  • the silicon fine particles may be fine particles in which at least two selected from the group consisting of single crystal silicon fine particles, polycrystalline silicon fine particles, and amorphous silicon fine particles are mixed.
  • the silicon fine particles in the present invention may be silicon fine particles in which a silicon oxide film is naturally or artificially formed after the silicon fine particles are produced. More preferable silicon fine particles are fine particles in which a silicon oxide film is formed on the surface of a silicon crystallite.
  • the silicon fine particles in the present invention may be particles obtained by crushing a lump of silicon simple substance (high purity silicon) or particles obtained by crushing particles of silicon simple substance.
  • silicon simple substance lump or particle is pulverized to produce silicon fine particles, the surface of the silicon fine particles is naturally oxidized to form a silicon oxide film.
  • the particle diameter of the silicon fine particles in the present invention is preferably 0.5 nm or more and 100 ⁇ m or less, more preferably 1 nm or more and 50 ⁇ m or less, more preferably 1
  • the thickness is from 5 nm to 10 ⁇ m, more preferably from 2 nm to 5 ⁇ m, and more preferably from 2.5 nm to 1 ⁇ m, from 5 nm to 500 nm, from 7.5 nm to 200 nm, from 10 nm to 100 nm. If the particle diameter is 500 nm or less, a suitable hydrogen generation rate and hydrogen generation amount can be obtained, and if it is 200 nm or less, a more preferable hydrogen generation rate and hydrogen generation amount can be obtained.
  • the aggregate of silicon fine particles in the present invention is an aggregate of the silicon fine particles. It may be naturally formed or artificially formed. Preferably, it is an aggregate obtained by agglomerating silicon fine particles on which a silicon oxide film is formed. Naturally formed aggregates are believed to remain aggregated in the gastrointestinal tract. A preferred aggregate has a structure in which voids are present inside and water molecules can enter the aggregate and react with the fine particles inside. Since the hydrogen generation rate of naturally formed aggregates does not depend on the aggregate size, the aggregate has a structure in which voids are inside and water molecules can enter the aggregate and react with the internal fine particles. Have
  • a preferable particle diameter of the aggregate of fine silicon particles is 10 nm or more and 500 ⁇ m or less. More preferably, they are 50 nm or more and 100 micrometers or less, More preferably, they are 100 nm or more and 50 micrometers or less. Aggregates can be formed to retain the surface area of the fine particles and can have a sufficient surface area to achieve high hydrogen generation capacity.
  • the particle diameter of the silicon fine particles constituting the aggregate of silicon fine particles in the present invention is preferably 0.5 nm to 100 ⁇ m, more preferably 1 nm to 50 ⁇ m, more preferably 1.5 nm to 10 ⁇ m, More preferably, they are 2 nm or more and 5 micrometers or less, More preferably, they are 2.5 nm or more and 1 micrometers or less, 5 nm or more and 500 nm or less, 7.5 nm or more and 200 nm or less, 10 nm or more and 100 nm or less.
  • the silicon fine particles constituting the silicon aggregate may be crystalline silicon fine particles or amorphous silicon fine particles.
  • a preferable aggregate is an aggregate of silicon crystallites having a crystallite diameter of 1 nm to 10 ⁇ m.
  • the aggregate is preferably an aggregate of silicon crystallites having a silicon oxide film formed on the surface.
  • the preventive or therapeutic agent of the present invention is preferably a silicon crystallite having a crystallite diameter of 1 nm to 1 ⁇ m, more preferably a crystallite diameter of 1 nm to 100 nm, on which a silicon oxide film is formed, And / or contains aggregates thereof.
  • an agglomerate of silicon crystallites having a silicon oxide film formed on the surface is contained as a main component.
  • the porous silicon particles may be a porous body of silicon particles. Moreover, the porous body by which the silicon fine particle was aggregated and processed may be sufficient.
  • the porous silicon particles are preferably particles made of porous silicon alone and having a silicon oxide film formed on the surface.
  • the porous silicon particles may be porous silicon particles having crystallinity. Further, it may be amorphous porous silicon particles having no crystallinity. When it has crystallinity, it may be single crystal or polycrystal.
  • the size of the voids present in the porous silicon particles can usually be 1 nm to 1 ⁇ m, and the porous silicon particles have a sufficient surface area to realize a high hydrogen generation capacity.
  • size of a porous silicon particle Preferably, it may be 200 nm to 400 ⁇ m.
  • the agglomerates of silicon fine particles and porous silicon particles are particles that have a large overall particle diameter and a large surface area, and are therefore suitable for oral administration. If the particles are large, they do not pass through the gastrointestinal tract, particularly the cell membrane and cells of the intestinal tract, and the silicon fine particles are not absorbed into the body, which is excellent from the viewpoint of safety.
  • the silicon fine particles in the present invention are preferably hydrophilized silicon fine particles.
  • the hydrophilized silicon fine particles can improve the contact efficiency between the surface and water, promote the hydrogen generation reaction, and generate a large amount of hydrogen.
  • the method of hydrophilic treatment is not particularly limited, and a known hydrophilic treatment method may be used. For example, hydrogen peroxide treatment and nitric acid treatment can be mentioned. Preferably, it is a peroxide treatment.
  • the hydrophilic treatment is preferably a treatment in which SiH groups of the silicon oxide film on the particle surface are removed and hydroxyl groups are added to the particle surface.
  • the particle surface is a surface of silicon fine particles, a surface of porous silicon particles, and a surface of silicon fine particles forming an aggregate of silicon fine particles.
  • silicon fine particles are immersed in hydrogen peroxide solution and stirred.
  • concentration of hydrogen peroxide is preferably 1 to 30%, more preferably 1.5 to 20%, still more preferably 2 to 15%, 2.5 to 10%, and most preferably 3%.
  • the time for immersion and stirring is preferably 5 to 90 minutes, more preferably 10 to 80 minutes, and still more preferably 20 to 70 minutes.
  • the hydrophilicity of the silicon fine particles can be improved by treating with hydrogen peroxide for 30 to 60 minutes. However, if the treatment time is increased, the hydrogen generation reaction from the silicon fine particles proceeds and the silicon fine particles are oxidized. Affects film thickness.
  • the temperature of the hydrogen peroxide solution during the treatment with the hydrogen peroxide solution is preferably 20 to 60 ° C., more preferably 25 to 50 ° C., more preferably 30 to 40 ° C., and most preferably 35 ° C.
  • the particle size distribution of silicon fine particles contained in the preventive or therapeutic agent of the present invention, the particle size distribution of fine particles composed of silicon alone, or the crystallite size distribution is not particularly limited. It may be polydispersed.
  • the preparation may contain silicon fine particles having a specific range of particle sizes or crystallite sizes. Moreover, there is no restriction
  • the method for producing silicon fine particles of the present invention is not particularly limited, but can be produced by physically pulverizing silicon-containing particles to a target particle diameter.
  • Suitable examples of the physical pulverization method include a bead mill pulverization method, a planetary ball mill pulverization method, a shock wave pulverization method, a high-pressure collision method, a jet mill pulverization method, or a pulverization method in which two or more of these are combined.
  • a suitable grinding method is a physical grinding method.
  • the fine particles made of fine silicon single particles are exposed to the atmosphere, the surface is oxidized and a silicon oxide film is formed.
  • the silicon oxide film may be artificially formed after pulverization by a known method such as chemical oxidation using an oxidizing agent such as hydrogen peroxide or nitric acid.
  • the size or particle size distribution of the target particles is obtained by appropriately changing the size and / or type of the beads. be able to.
  • the starting silicon-containing particles are not limited as long as they are high-purity silicon particles.
  • high-purity silicon particle powder is mentioned.
  • the starting silicon-containing particles may be single crystal, polycrystalline or amorphous.
  • the present invention is a preventive or therapeutic agent for diseases caused by oxidative stress.
  • Agents for preventing or treating diseases caused by oxidative stress include agents for preventing diseases caused by oxidative stress, agents for treating diseases caused by oxidative stress, and agents for preventing and treating diseases caused by oxidative stress included.
  • the preventive or therapeutic agent of the present invention has effects such as prevention of symptom onset, improvement of symptom, suppression of hate of symptom, prevention of recurrence of symptom, etc. for one or more symptoms related to a disease caused by oxidative stress.
  • the preventive or therapeutic agent for diseases caused by oxidative stress of the present invention can also be referred to as a therapeutic agent for diseases caused by oxidative stress.
  • the prophylactic or therapeutic agent and the treatment agent have the same meaning. Therefore, the treatment agent for diseases caused by oxidative stress according to the present invention includes an agent for preventing diseases caused by oxidative stress, an agent for treating diseases caused by oxidative stress, and prevention and treatment of diseases caused by oxidative stress. Agent to be included.
  • the treatment agent of this invention has effects, such as prevention of onset of a symptom, improvement of a symptom, suppression of hate of a symptom, prevention of recurrence of a symptom, about one or more symptoms concerning a disease resulting from oxidative stress.
  • the present application also relates to an invention for a method for treating a disease caused by oxidative stress, characterized by administering a drug containing silicon fine particles.
  • the treatment method is a concept including a prevention method and a treatment method.
  • the present invention provides a method for preventing and / or treating a disease caused by oxidative stress by administering a drug containing silicon fine particles to a human or a non-human animal.
  • the present invention provides a method for preventing the onset of symptoms, a method for improving symptoms, a method for suppressing aversion of symptoms, and a method for preventing recurrence of symptoms for one or more symptoms related to a disease caused by oxidative stress. To do.
  • the disease caused by oxidative stress is a disease and symptom involving active oxygen generated in vivo, particularly hydroxyl radical having strong oxidizing power, and is caused by a hydroxyl radical and generating a hydroxy radical.
  • the disease caused by oxidative stress in the present invention does not include kidney disease. Kidney diseases include chronic renal failure, renal fibrosis, acute kidney injury, renal ischemia reperfusion injury, drug-induced kidney injury, chronic kidney disease and the like.
  • the silicon fine particles in the present invention have the property of continuously generating hydrogen for a long time (20 hours or more) in vitro.
  • the silicon fine particles come into contact with water having a pH of 7 or more, hydrogen is generated, and more hydrogen is generated at a pH of 8 or more.
  • it has the property of hardly generating hydrogen at pH 5 or lower.
  • the silicon fine particles in the present invention When the silicon fine particles in the present invention are orally administered, it is considered that almost no hydrogen is generated in the stomach due to the above properties, but hydrogen is generated in the intestine.
  • the silicon microparticles according to the present invention were administered to normal mice, hydrogen generation was confirmed in the cecum, which is a part of the large intestine. Even when a normal mouse was fed under the same conditions, hydrogen was below the detection limit. Since the residence time of food in the intestine is usually 20 hours or more in humans, the preventive or therapeutic agent of the present invention continues to generate hydrogen in the intestine for a long time by being orally administered. Can be distributed.
  • hydrogen can be delivered to the body for a long time by transdermal or transmucosal by placing the silicon fine particles on the skin or mucous membrane for a long time.
  • One of the mechanisms of action for preventing and / or treating diseases caused by oxidative stress is that the silicon fine particles in the present invention continue to generate hydrogen over a long period of time, and the generated hydrogen is transported into the blood and organs. This is thought to be due to the selective reaction of hydrogen with hydroxyl radicals. Moreover, since the antioxidant power in blood is improving, it is thought to be due to the antioxidant substance produced in blood. Furthermore, since the remarkable effect is shown compared with hydrogen water, there exists another effect
  • a protein containing a metal element such as cobalt captures a protein that has a strong reducing power as a result of hydrogen atoms donating electrons.
  • a mechanism is considered that is transported to each organ, reacts with the hydroxyl radical, and disappears.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for inflammatory diseases.
  • An inflammatory disease is mentioned as a disease resulting from oxidative stress.
  • Inflammatory diseases are diseases accompanied by inflammatory symptoms. In inflammatory diseases, the amount of inflammatory cytokine production increases, and the concentration of inflammatory cytokines in the blood increases.
  • the preventive or therapeutic agent of the present invention can suppress the production of inflammatory cytokines. Inflammation includes inflammation that develops systemically and inflammation that develops locally. Examples of systemic inflammation include sepsis, systemic inflammatory response syndrome (SIRS), endotoxemia, and the like. Examples of local inflammation include inflammatory diseases of the digestive tract, arthritis, dermatitis, hepatitis and the like.
  • the present invention can be one of the causal therapies for inflammatory diseases.
  • the preventive or therapeutic agent of the present invention can be a preventive or therapeutic agent for systemic inflammatory diseases.
  • the present invention can also be a preventive or therapeutic agent for sepsis.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for inflammatory diseases of the digestive tract.
  • the digestive tract is a tube through which food connected from the mouth to the anus passes, and includes the esophagus, stomach, duodenum, small intestine, large intestine and the like.
  • Inflammatory diseases of the gastrointestinal tract include inflammatory diseases at each location. Examples include inflammatory bowel disease, gastric ulcer, and duodenal ulcer. Inflammatory bowel diseases include ulcerative colitis, Crohn's disease, Behcet's disease and the like.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for inflammatory bowel disease.
  • the preventive / therapeutic agent of the present invention can be a prophylactic or therapeutic agent for ulcerative colitis.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect in inflammatory bowel disease. The effect is significantly better than hydrogen water.
  • the silicon fine particles in the present invention reduces visceral discomfort and visceral pain (abdominal pain, etc.) associated with inflammatory bowel disease. This is because nerve activation of the vagus nerve dorsal motor nucleus and solitary tract nucleus of the medulla that respond to visceral discomfort and visceral pain and the central nucleus of the amygdala are suppressed by the silicon fine particles.
  • the antioxidant power in blood can be improved. It was confirmed that lipid oxidation in the blood of inflammatory bowel disease model mice administered with silicon microparticles was suppressed.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for arthritis.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect in arthritis.
  • the arthritis in this specification includes arthritis caused by rheumatism, bacterial arthritis, and arthritis caused by trauma. Examples include rheumatoid arthritis, tuberculosis arthritis, psoriatic arthritis, spondyloarthritis and the like.
  • the prophylactic or therapeutic agent of the present invention can be preferably a prophylactic or therapeutic agent for rheumatoid arthritis.
  • the preventive or therapeutic agent of the present invention can be an onset inhibitor of arthritis.
  • the prophylactic / therapeutic agent of the present invention can be an agent for reducing joint swelling associated with arthritis.
  • the number of arthritis patients has increased in recent years with the aging of the population and the increase in obesity, and finding the causal therapy for arthritis greatly contributes to future medical care and health promotion.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for dermatitis.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect in dermatitis.
  • the dermatitis in this specification includes contact dermatitis, allergic contact dermatitis, contact urticaria and the like.
  • the preventive or therapeutic agent of the present invention may be a preventive or therapeutic agent for contact dermatitis.
  • the preventive or therapeutic agent of the present invention can be an agent for suppressing swelling and / or thickening of the inflamed part of dermatitis.
  • the preventive or therapeutic agent of the present invention can be an inhibitor of swelling and / or thickening of the inflamed part in contact dermatitis.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for hepatitis.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect in hepatitis.
  • the hepatitis in this specification includes acute hepatitis and chronic hepatitis.
  • the hepatitis in this specification includes alcoholic hepatitis, viral hepatitis, drug-induced hepatitis and the like.
  • the concept of acute hepatitis in the present specification includes fulminant hepatitis with significant liver damage.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for acute hepatitis.
  • the preventive or therapeutic agent of the present invention may be a prophylactic or therapeutic agent for fulminant hepatitis. Finding the cause therapy for hepatitis greatly contributes to future medical care and health promotion.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for visceral discomfort.
  • the silicon fine particles in the present invention exhibit a preventive and / or therapeutic effect excellent in visceral discomfort.
  • visceral discomfort includes visceral pain, vomiting, nausea, diarrhea, belly and the like.
  • the prophylactic or therapeutic agent of the present invention may be at least one prophylactic or therapeutic agent selected from the group consisting of visceral pain, vomiting, nausea, belly, and diarrhea.
  • Visceral pain includes abdominal pain (upper abdominal pain, side abdominal pain, etc.), back pain, shoulder pain and the like.
  • the vagus nerve dorsal motor nucleus and solitary nucleus in the dorsal medulla are involved in visceral discomfort, visceral pain and gastrointestinal motility.
  • the dorsal motor nucleus and solitary nucleus of the vagus nerve are regions in the brain that are involved in visceral perception such as visceral pain.
  • the central amygdala is involved in pain such as visceral pain. Vomiting centers are involved in vomiting and nausea.
  • the preventive or therapeutic agent of the present invention can suppress activation of the vagus nerve dorsal motor nucleus, solitary nucleus, amygdala central nucleus, and vomiting center.
  • Visceral pain, vomiting, nausea, diarrhea, and wheezing are the main symptoms of diseases that cause abnormal activities of the gastrointestinal tract. By improving these symptoms, the quality of life of patients is greatly improved.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for visceral discomfort associated with inflammatory diseases of the digestive tract.
  • visceral pain eg, abdominal pain
  • diarrhea are the main symptoms, but administration of the silicon particles in the present invention greatly improves patient distress.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for visceral discomfort associated with inflammatory bowel disease.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for visceral pain associated with inflammatory bowel disease.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for abdominal pain associated with inflammatory bowel disease.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for visceral discomfort associated with administration of an anticancer agent. Visceral discomfort associated with the administration of anticancer agents includes vomiting, nausea, diarrhea, visceral pain and the like.
  • the prophylactic or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for nausea or vomiting associated with administration of an anticancer agent.
  • Known anticancer agents in which vomiting and nausea are likely to appear as side effects, are platinum preparations, alkylating agents, camptothecin-based topoisomerase inhibitors, anthracycline-based anticancer antibiotics, and the like.
  • the prophylactic or therapeutic agent of the present invention can be preferably a prophylactic or therapeutic agent for nausea or vomiting associated with administration of a platinum preparation.
  • the present invention is excellent in the effect of reducing or preventing visceral discomfort and excellent in safety.
  • the symptoms of visceral discomfort are reduced or prevented, improving the patient's quality of life.
  • anticancer drug treatment can be continued.
  • the present invention finds a causal therapy for visceral discomfort and greatly contributes to future treatment of visceral discomfort and cancer treatment.
  • the prophylactic or therapeutic agent of the present invention may be a prophylactic or therapeutic agent for depression or depression.
  • the silicon fine particles in the present invention exhibit a prophylactic and / or therapeutic effect excellent in depression or depression.
  • Symptoms of depression include depressed mood, sleep disorder, loss of interest / joy, appetite disorder, reduced thinking / concentration / decision, valuelessness, self-responsibility, fatigue, and reduced spirit.
  • diagnostic criteria for depression ICD (International Statistical Classification of Diseases and Related Health and Problems) and DSM (Diagnostic and Manual Manual of Mental Disorders) are used.
  • the depression or depression in the present invention includes a relatively mild symptom that is not diagnosed as depression according to diagnostic criteria, and depression associated with other diseases (for example, depression associated with anxiety disorder, cancer Accompanying depression).
  • Depression and depression are diseases that have increased in recent years, and have found a causative treatment for depression or depression because of low remission rate and high relapse rate even after remission. This will greatly contribute to future medical care and health promotion.
  • the preventive or therapeutic agent of the present invention can be a preventive or therapeutic agent for Parkinson's disease.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect on Parkinson's disease.
  • the preventive or therapeutic agent of the present invention can be an agent for improving motor symptoms of Parkinson's disease. Parkinson's disease patients have increased in recent years with the aging of the population. Finding the causal treatment of Parkinson's disease, because it is a disease without a radical cure, greatly contributes to future medical care and health promotion.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for autism spectrum disease.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect on autism spectrum disease.
  • Symptoms of the autism spectrum include communication disorders (can't communicate their feelings well), social interaction disorders (can't read other person's feelings), limited behavior, interest, Activities (stickiness), and hypersensitivity / sensation (bottle / donkan) are included.
  • autism spectrum disease includes autism (autistic disorder), Asperger's syndrome, childhood disintegrative disorder, and unspecified pervasive developmental disorder.
  • the prophylactic or therapeutic agent of the present invention can be preferably a prophylactic or therapeutic agent for social communication disorders.
  • the preventive or therapeutic agent of the present invention can be a preventive or therapeutic agent for memory impairment.
  • the silicon fine particles in the present invention exhibit a preventive and / or therapeutic effect excellent in memory impairment.
  • Memory impairment in this specification includes dementia, mild cognitive impairment (MCI), cognitive impairment associated with underlying diseases (for example, cognitive impairment associated with inflammatory diseases such as collagen disease and infection), and the like.
  • the preventive or therapeutic agent of the present invention may be a preventive or therapeutic agent for dementia or mild cognitive impairment.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for spinal cord injury.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect on spinal cord injury.
  • the spinal cord injury in this specification includes, for example, complete injury, incomplete injury and the like.
  • Various symptoms after spinal cord injury include motor dysfunction, sensory dysfunction, bladder dysfunction, rectal dysfunction, respiratory dysfunction, and numbness.
  • the prophylactic or therapeutic agent of the present invention can be preferably a prophylactic or therapeutic agent for motor dysfunction associated with spinal cord injury.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for hearing loss.
  • the silicon fine particles in the present invention exhibit a preventive and / or therapeutic effect excellent in hearing loss.
  • Hearing loss in the present specification is a pathological condition in which hearing is reduced, and includes noise-induced hearing loss, hearing loss due to cerebral infarction, hearing loss due to infection, presbycusis, and hearing loss due to side effects of drugs.
  • the prophylactic or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for noise-induced hearing loss.
  • the number of patients with hearing loss has increased in recent years, and finding a causal treatment for hearing loss is a disease that does not have a radical cure, which greatly contributes to future medical care and health promotion.
  • the prophylactic or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for cerebral ischemic injury or reperfusion injury after cerebral ischemia.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect on damage due to cerebral ischemia and / or reperfusion damage after cerebral ischemia.
  • the disorder caused by cerebral ischemia or the reperfusion disorder after cerebral ischemia in this specification is caused when the brain suffers an ischemic state due to cerebral infarction or the like, or when blood reperfusion occurs.
  • reperfusion of blood may spread not only locally but also to distant organs and cause damage.
  • the number of patients suffering from dementia due to ischemia or reperfusion after ischemia, motor dysfunction, etc. has increased, and we found a causal treatment for damage due to cerebral ischemia or reperfusion injury after cerebral ischemia This will greatly contribute to future medical care and health promotion.
  • the preventive or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for diabetes.
  • the silicon fine particles in the present invention exhibit an excellent preventive and / or therapeutic effect on diabetes. Diabetes in this specification includes all types of diabetes including type 1 diabetes, type 2 diabetes and gestational diabetes.
  • the prophylactic or therapeutic agent of the present invention can be preferably a prophylactic or therapeutic agent for type 2 diabetes.
  • Diabetes patients have been increasing in recent years with the aging of the population and the increase in obesity, and finding causal therapies for diabetes greatly contributes to future medical care and health promotion.
  • the prophylactic or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for hangover.
  • the silicon microparticles in the present invention exhibit an excellent preventive and / or therapeutic effect on hangover, the preventive or therapeutic agent of the present invention prevents the onset of at least one symptom of hangover, suppresses ashamed, recovers early, or improves To do.
  • Symptoms of hangover include headache, sleep disturbance, nausea, nausea / vomiting, hand tremor, cognitive impairment, sensory disturbance, depression, autonomic symptoms and the like.
  • the discovery of hangover causal therapy greatly contributes to future medical care and health promotion.
  • the prevention or treatment targets of the prevention or treatment agent of the present invention are humans and non-human animals.
  • Preferred non-human animals include pets and livestock.
  • One or more of the silicon fine particles in the present invention may be administered to humans or non-human animals as they are, but if necessary, they are mixed with an acceptable additive or carrier and are well known to those skilled in the art. It can be formulated into a form and administered.
  • additives or carriers include, for example, pH adjusters (eg, sodium bicarbonate, sodium carbonate, potassium carbonate, citric acid, etc.), excipients (eg, sugar derivatives such as mannitol, sorbitol; corn starch, Starch derivatives such as potato starch; or cellulose derivatives such as crystalline cellulose), lubricants (eg, metal stearates such as magnesium stearate; or talc), binders (eg, hydroxypropylcellulose, hydroxypropyl) Methyl cellulose, polyvinyl pyrrolidone, etc.), disintegrating agents (eg, cellulose derivatives such as carboxymethyl cellulose, carboxymethyl cellulose calcium), preservatives (eg,
  • the administration route of the preventive or therapeutic agent of the present invention is not particularly limited, but preferred administration routes include oral, transdermal, transmucosal (oral cavity, rectum, vagina, etc.).
  • preparations for oral administration include tablets, capsules, granules, powders, syrups (dry syrups), oral jellys, and the like.
  • preparations for transdermal administration or transmucosal administration include patches and ointments.
  • Tablets, capsules, granules, powders, etc. can be made into enteric preparations.
  • an enteric coating is applied to tablets, granules and powders.
  • a poorly gastric enteric coating agent can be used.
  • the capsule can be made enteric by filling the enteric capsule with the silicon fine particles of the present invention.
  • the hydrogen generation rate can be adjusted by adjusting the particle size and particle size distribution of the silicon fine particles.
  • the prophylactic or therapeutic agent of the present invention can be administered to a human or non-human animal after being formulated into the above dosage form.
  • the content of silicon fine particles in the preventive or therapeutic agent of the present invention is not particularly limited, and examples thereof include 0.1 to 100% by weight, 1 to 99% by weight, and 5 to 95%.
  • the dose and frequency of administration of the silicon microparticles in the present invention are appropriately determined depending on the conditions such as the subject of administration, age, weight, sex, purpose (for prevention or treatment), severity of symptoms, dosage form, administration route and the like. It can change.
  • the preferred dosage of silicon microparticles is, for example, about 0.1 mg to 10 g, preferably about 1 mg to 5 g, more preferably about 1 mg to 2 g per day.
  • count of administration may be once or several times per day, or once in several days. For example, it may be 1 to 3 times, 1 to 2 times, or 1 time per day.
  • the preventive or therapeutic agent for diseases (excluding kidney disease) caused by oxidative stress containing the silicon fine particles of the present invention can be used for pharmaceuticals, quasi drugs, medical devices, hygiene products, foods, and beverages. it can.
  • the present application also relates to an invention of a pharmaceutical composition for preventing or treating diseases caused by oxidative stress containing silicon fine particles (excluding kidney diseases).
  • the present application also relates to an invention of a pharmaceutical composition containing a preventive or therapeutic agent for diseases caused by oxidative stress (excluding kidney diseases) containing the silicon fine particles.
  • the pharmaceutical composition in the present invention includes a composition having a moderate action corresponding to a quasi-drug.
  • Embodiments of the pharmaceutical composition of the present invention can include embodiments of the invention relating to the above-mentioned preventive or therapeutic agent.
  • the present application also relates to an invention of a medical device containing a preventive or therapeutic agent for a disease (excluding kidney disease) caused by oxidative stress containing the silicon fine particles. Further, the present invention relates to an invention of a medical device for prevention or treatment of diseases caused by oxidative stress containing silicon fine particles (excluding kidney diseases).
  • the medical device in the present invention is a tool or instrument intended to be used for treatment or prevention of diseases of humans or non-human animals.
  • An example of the medical device is a mask. By wearing the mask of the present invention, hydrogen can be supplied directly to the trachea or lung. Another example is a bandage.
  • This application also relates to the invention of a sanitary article for prevention of diseases (excluding kidney diseases) caused by oxidative stress containing silicon fine particles.
  • Embodiments of the present invention can include embodiments of the invention relating to the above-mentioned preventive or therapeutic agents.
  • the sanitary product of the present invention may be a tool or a product that comes into contact with the skin or mucous membrane of a human or non-human animal, and includes those classified as quasi drugs. For example, diapers and sanitary products can be mentioned.
  • the present application also relates to an invention of a food or beverage containing a preventive or therapeutic agent for diseases (excluding kidney diseases) caused by oxidative stress containing the silicon fine particles.
  • the present invention relates to a food or beverage for prevention or treatment of diseases (excluding kidney diseases) caused by oxidative stress containing the silicon fine particles.
  • the food or beverage of the present invention include health food, functional display food, food for specified health use and the like.
  • the form of the food or beverage For example, the form of the mixture mixed with the existing foodstuff and drink, and the form which was formulated can be mentioned. For example, a tablet, a capsule, a powder, a granule, a jelly, etc. are mentioned.
  • Example 1 200 g of high-purity silicon powder (manufactured by High-Purity Chemical Laboratory Co., Ltd., particle size distribution ⁇ 5 ⁇ m (however, silicon particles having a crystal particle diameter exceeding 1 ⁇ m), purity 99.9%) was added to 4 L (liter) of 99.5 wt% ethanol solution. ) Zirconia beads (capacity: 750 ml) with a diameter of 0.5 ⁇ m added, and rotated for 4 hours using a bead mill apparatus (manufactured by Imex Corporation, horizontal continuous ready mill (model, RHM-08)). Pulverization (one-step pulverization) was performed at a number of 2500 rpm to refine the structure.
  • the ethanol solution containing the refined silicon particles was separated from the beads by a separation slit provided inside the grinding chamber of the bead mill apparatus, and then heated to 30 ° C. to 35 ° C. using a vacuum evaporator. By evaporating the ethanol solution, fine silicon particles (crystallites) were obtained.
  • the refined silicon particles (crystallites) obtained by the above method mainly have a crystallite diameter of 1 nm or more and 100 nm or less, and most crystallites formed aggregates.
  • the crystallites were covered with a silicon oxide film, and the thickness of the silicon oxide film was about 1 nm.
  • the mode diameter was 6.6 nm
  • the median diameter was 14.0 nm
  • the average crystallite diameter was 20.3 nm. .
  • the obtained mixture of silicon crystallites and aggregates of the silicon oxide film on which the silicon oxide film is formed is an embodiment of silicon fine particles that are the active ingredients of the present invention.
  • Example 2 The silicon crystallites and the aggregates obtained in Example 1 were mixed with hydrogen peroxide (3 wt%) in a glass container and stirred at 35 ° C. for 30 minutes. The silicon crystallites and aggregates treated with hydrogen peroxide were removed from the hydrogen peroxide by solid-liquid separation using a known centrifugal separator. Further thereafter, the obtained silicon crystallites and aggregates thereof and an ethanol solution (99.5 wt%) were mixed and sufficiently stirred. The silicon crystallites and the aggregates mixed with the ethanol solution were sufficiently dried after removing the highly volatile ethanol solution by solid-liquid separation using a known centrifugal separator.
  • the resulting mixture of silicon crystallites formed with a hydrogen peroxide solution and formed with a silicon oxide film and aggregates thereof is an embodiment of silicon fine particles that are active ingredients of the present invention.
  • the hydrogen generation rate of the obtained silicon crystallite aggregates did not depend on the aggregate size.
  • the hydrogen generation amount of the silicon fine particles (silicon crystallites and aggregates thereof) obtained in Example 2 was measured. 10 mg of silicon fine particles were put into a glass bottle with a capacity of 100 ml (a borosilicate glass thickness of about 1 mm, a Laboran screw tube made by ASONE). Water adjusted to pH 8.2 with sodium hydrogen carbonate was put into this glass bottle, the liquid temperature was sealed at a temperature of 36 ° C., and the hydrogen concentration in the liquid in the glass bottle was measured. A portable dissolved hydrogen meter (manufactured by Toa DKK Co., Ltd., model DH-35A) was used for measuring the hydrogen concentration. The amount of hydrogen generation per gram of silicon fine particles is shown in FIG.
  • Example 3 Aggregates were separated from the silicon crystallites obtained in Example 2 and the mixture of the aggregates.
  • the obtained agglomerates of silicon crystallites are an embodiment of silicon fine particles that are active ingredients of the present invention.
  • An electron scanning microscope (SEM) photograph of the obtained silicon crystallite aggregate is shown in FIG.
  • Example 4 One-step grinding was performed in the same manner as in Example 1.
  • the ⁇ 0.5 ⁇ m zirconia beads (capacity 750 ml) used for the one-step grinding were automatically separated from the solution containing silicon crystallites in the inside of the bead mill grinding chamber.
  • 0.3 ⁇ m zirconia beads (capacity 750 ml) were added, and the silicon crystallites were further pulverized (two-step pulverization) at a rotation speed of 2500 rpm for 4 hours.
  • the beads were separated from the solution containing silicon crystallites as described above, and the obtained ethanol solution containing silicon crystallites was heated to 40 ° C. using a vacuum evaporator as in Example 1. Ethanol evaporated and silicon crystallites crushed in two steps were obtained.
  • the silicon crystallite on which the silicon oxide film pulverized in two steps is formed is also an embodiment of the silicon fine particles that are the active ingredients of the present invention.
  • Example 5 A mixture of silicon crystallites formed with the hydrogen peroxide-treated silicon oxide film obtained in Example 2 and aggregates thereof was filled into a commercially available capsule No. 3 to obtain a capsule preparation.
  • This capsule preparation is mainly composed of an aggregate of silicon crystallites formed with a silicon oxide film treated with hydrogen peroxide solution, and further includes silicon crystallites formed with a silicon oxide film treated with hydrogen peroxide solution. contains.
  • ⁇ Test example> I Preparation of silicon fine particle-containing food Normal feed (Oriental Yeast Industry Co., Ltd., model number AIN93M) was mixed with silicon fine particles (silicon crystallites and aggregates thereof) produced in Example 2 so as to be 2.5 wt%. . Further, an aqueous citric acid solution (pH 4) was added in an amount of about 0.5 wt% with respect to the total amount of the silicon fine particles and the feed, and kneaded using a known kneading apparatus to obtain a silicon fine particle-containing food. .
  • aqueous citric acid solution pH 4
  • the silicon fine particle-administered group was fed with the above-mentioned silicon fine particle-containing food, and the control group was fed with a normal feed (normal food) (Oriental Yeast Co., Ltd., model number AIN93M).
  • Blood was collected after administration for 8 weeks, and the antioxidant power of plasma (BAP test) (free radical analyzer FREE Carrio Duo) was evaluated. The results are shown in FIG. It was shown that the antioxidant power was significantly increased in the silicon microparticle administration group.
  • C Pharmacological test in mouse model of inflammatory bowel disease
  • C-1 Preparation of Inflammatory Bowel Disease Model Mice C57B16 / J mice (male 7 weeks old, body weight 24-25 g) were obtained from Japan SLC.
  • the silicon fine particle-administered group was fed with the above-mentioned silicon fine particle-containing food, and the control group was fed with a normal feed (normal food) (Oriental Yeast Co., Ltd., model number AIN93M). From the day (1d) the day after the start of each diet (0d), free drinking water of 5% dextran sulfate sodium (DSS) (MP Bio) was started in the silicon microparticle administration group and the control group, and inflammatory bowel disease A model mouse was prepared.
  • DSS dextran sulfate sodium
  • This model is a standard model for inflammatory bowel disease. Antioxidant power, weight loss, colitis score (Table 1), survival rate, biopsy examination findings (colon length, condition), histopathological analysis, neural activity involved in visceral discomfort and visceral pain, The usefulness of silicon fine particles was evaluated by comparison with hydrogen water.
  • LPO Lipid hydroxide
  • HEL hexanoyl lysine
  • Hexanoyllysine is an oxidative stress biomarker that can capture the early stages of lipid peroxidation.
  • the measurement results are shown in FIG. It was shown that the generation of LPO and the generation of HEL were suppressed by the administration of silicon fine particles, and that the antioxidant power in blood was improved by the administration of silicon fine particles.
  • Fig. 6 shows the results of weight loss, colitis score, and survival rate.
  • the silicon fine particle-administered group significantly suppressed the weight loss and the progression of colitis and had a higher probability of survival than the control group.
  • the disease state of the developed inflammatory bowel disease worsened, whereas in the silicon microparticle-administered group mice, the worsening of inflammatory bowel disease was significantly suppressed.
  • Biopsy examination The biopsy examination was performed by cutting the ileum and removing the anus from the cecum and measuring the length of the large intestine (the length of the colon to the rectum). On the third day after DSS administration (3d), 8 mice and 8 control groups were extracted, and on the 5th day after DSS administration (5d), 7 silicon particles administration groups and 8 control groups were extracted. Similarly, the ileum was cut from 4 wild-type groups and the anus was removed from the cecum.
  • FIG. 7 shows a comparison of the length of the large intestine (the length of the colon to the rectum) between the control group and the silicon fine particle administration group. On the third day (3d) and the fifth day (3d), it was shown that the silicon administration group was significantly longer.
  • FIG. 7 shows a photograph of the anus from the cecum extracted. In both 3d and 5d, bleeding was observed in the lower rectum of the control mouse, but no bleeding was observed in the silicon microparticle-administered mice.
  • FIG. 8 shows a comparison of the length of the large intestine (the length of the colon to the rectum) of the wild type group, the 3d control group, and the 3d silicon microparticle administration group. Compared to the wild-type group, the control group silicon-administered group showed that the large intestine was significantly shortened, and the silicon-administered group showed that the shortening of the large intestine was suppressed.
  • FIG. 8 shows photographs of the anus from the cecum extracted from each group of mice.
  • FIGS. 9 to 11 show the results of histopathological analysis.
  • FIG. 9 shows the day 3 (3d) colon and rectum.
  • FIG. 10 shows the colon and rectum on day 5 (5d).
  • FIG. 11 shows the result of analyzing the degree of crypt collapse.
  • colitis such as fold fallout / disappearance, vacuolation of mucosal epithelial tissue, and disappearance of crypts, but the administration of silicon microparticles alleviated these colitis symptoms. It was shown that. The degree of crypt collapse was suppressed to less than half.
  • C-6 Inhibition of neuronal activation related to visceral pain and visceral discomfort
  • c-Fos expression is applied to the nerve activation of the medullary dorsal region and amygdala. The indicator was evaluated.
  • perfusion fixation was performed with 0.1M phosphate buffer containing 4% paraformaldehyde. After anti-ice crystal treatment with 0.1M phosphate buffer containing 30% sucrose, it was frozen with powdered dry ice.
  • a 30 ⁇ m-thick section was prepared with a microtome (cryostat), and fluorescent immunostaining was performed by a floating method. After blocking treatment with 0.01M phosphate buffer containing 3% bovine serum albumin protein (BSA) and 0.3% Triton-X, primary antibody, anti-c-Fos antibody (Rabbit polyclonal antibody) (Abcam) was suspended in blocking solution at 1000-fold dilution. The sample was reacted overnight in this primary antibody reaction solution. After washing with 0.01 M phosphate buffer, the secondary antibody, Alexa Fluor (registered trademark) 488-conjugated anti-rabbit IgG antibody (Thermo Fisher Scientific) was diluted 500 times with 0.01 M phosphate buffer. In the secondary antibody reaction solution, the sample was allowed to react in the dark for 1 hour. After washing with 0.01 M phosphate buffer, the sample was sealed and observed with a fluorescence microscope.
  • BSA bovine serum albumin protein
  • Triton-X Triton-X
  • FIG. 12 shows a fluorescent immunostaining photograph of the medullary dorsal side.
  • a white signal indicates c-Fos positive cells.
  • Con is the medullary dorsal side of a control model mouse
  • Si is the medullary dorsal side of a model mouse to which silicon fine particles are administered.
  • 12N represents the hypoglossal nucleus
  • AP represents the last cortex
  • CC represents the central tube. Circles indicate the location of the vagus nerve dorsal motor nucleus and solitary nucleus responding to visceral discomfort and visceral pain.
  • mice with normal diet whereas mice with diet containing silicon fine particles had few positive cells, and the activity of vagus nerve dorsal motor nucleus and solitary nucleus were significantly suppressed. . Therefore, it was shown that visceral discomfort and visceral pain (abdominal pain) were suppressed by the silicon fine particles. Since the drawing is grayscale, the green fluorescence signal is shown as a white signal.
  • FIG. 13 shows a fluorescent immunostaining photograph of the amygdala.
  • a white signal indicates c-Fos positive cells.
  • Con is the amygdala of the control model mouse
  • Si is the amygdala of the model mouse administered with silicon fine particles
  • the upper two upper and lower sheets are the left amygdala of the same mouse
  • the lower is the right amygdala.
  • the arrow points to the central nucleus of the amygdala that reacts to pain such as visceral pain.
  • c-Fos positive cells were observed in the central nucleus of the amygdala, and a visceral pain response was observed.
  • Hydrogen water was produced using a high-concentration hydrogen water generator (Lourdes Victory Japan Co., Ltd.). 1.7 L of tap water was put into the generator and 30 minutes (0.8 to 1.2 ppm hydrogen water preparation course) was selected. As soon as hydrogen water production was completed, it was put in a glass bottle with a screw cap and covered with aluminum foil. The dissolved hydrogen concentration of the produced hydrogen water was measured (dissolved hydrogen concentration determination reagent (MIZ Co., Ltd.): methylene blue reagent). The results are shown in FIG. Hydrogen produced in the hydrogen water gradually diffused and became undetectable after 6 hours.
  • MIZ Co., Ltd. methylene blue reagent
  • the prepared hydrogen water was mixed with DSS (5%), and mice were allowed to drink freely every day. Hydrogen water was changed twice a day (around 9am and 6pm). Hydrogen water was newly prepared for each exchange, and DSS (5%) was mixed.
  • FIG. 15 shows the average value of the difference between the average length of the large intestine in the wild type group and the length of the individual large intestine in each group as the degree of shortening of the large intestine in each group.
  • Sensitization was performed by intradermally administering the above-described sensitizing antigen solution 0.025 ml / dose / mouse to the auricle base (8 weeks of age: 1st time) and ridge (11 weeks of age: 2nd time). The total amount of collagen per animal is 0.2 mg). Two to four weeks after the second sensitization day, the mouse exhibited inflammation in the knee joint.
  • the average value of the arthritis index of each mouse (each limb) in each mouse is defined as the arthritis index (average of all limbs) of each individual, and the average value of the arthritis index (average of all limbs) of each individual in each group is shown in FIG. It was shown to.
  • solid is the arthritis index (maximum inflammatory limb) of each mouse
  • solid in each group was shown in FIG. 18 for every week. .
  • the horizontal axis in FIGS. 17 and 18 represents the time (weeks) from the second sensitization. In comparison with the normal group, inflammation was suppressed in the group containing silicon fine particles.
  • the silicon fine particles in the present invention exhibit a high preventive effect and a high therapeutic effect against arthritis.
  • the first and second sensitization is performed by directly applying dinitrofluorobenzene (DNBF) solution (suspended in an equal amount of olive oil) to the left and right ears on the front chest skin. went. After the pinna sensitization, the pinna was inflamed and thickened.
  • DNBF dinitrofluorobenzene
  • the thickness of the auricle was measured every day for 3 days from the day of the third sensitization (Day 7) (Day 7 (Day 1) to Day 9 (Day 3)).
  • the thickness of the left and right pinna was measured three times with a micrometer (variable measuring force type digimatic micrometer), and the average value was defined as the pinna thickness.
  • the thickness of the auricle from the first day to the third day is shown in FIG. Compared with the control group fed the normal diet, the thickening of the auricle was suppressed in the silicon microparticle administration group.
  • the difference in ear thickness between days is defined as the thickness, the difference in ear thickness on the first and second days, the difference in ear thickness on the second and third days, and the ear on the first and third days
  • the difference in thickness is shown in FIG.
  • the degree of thickening it was shown that thickening was suppressed in the group administered with silicon fine particles compared to the control group.
  • the silicon fine particles in the present invention exert a high preventive effect and a high therapeutic effect against inflammation of contact dermatitis.
  • the survival rate of the mice was confirmed and evaluated.
  • the experiment was performed 4 times, and 5-6 animals per group were examined in one experiment.
  • the survival rate (about 80%) of the silicon microparticle administration group was significantly higher than that of the control group mice (35%) (FIG. 21).
  • the silicon fine particles in the present invention exert a high preventive effect and a high therapeutic effect against acute hepatitis.
  • c-Fos Neural activation of the vomiting center on the dorsal side of the medulla was evaluated using the expression of c-Fos as an index as follows. On the day after cisplatin administration (16 hours or longer), model mice were fixed by perfusion with 4% paraformaldehyde fixative to prepare frozen specimens. A 30 ⁇ m-thick frozen section was prepared, and c-Fos positive cells (active neurons) in brain tissue were identified by fluorescent immunostaining using an anti-c-Fos antibody (1000-fold dilution: Abcam). .
  • FIG. 22 shows the results of fluorescent immunostaining on the dorsal side of the medulla. Red fluorescent signal indicates c-Fos positive cells. In normal-fed mice (FIG.
  • the number of c-Fos positive cells was counted in the c-Fos immunostaining result photograph.
  • the number of positive cells in 3 sections per individual was counted, and the average was taken as the number of positive cells in that individual.
  • the average of 8 mice was defined as the number of positive cells in the group.
  • the results are shown in FIG.
  • the activation of the vomiting center was greatly suppressed by silicon fine particles.
  • the silicon fine particles in the present invention exert a high preventive effect and a high therapeutic effect against nausea or vomiting as a side effect of the anticancer agent.
  • a behavioral test (tail suspension test, forced swimming test, and spontaneous activity measurement) was performed 24 hours after administration of LPS or physiological saline (Day 7).
  • the tail suspension test and forced swimming test are behavioral tests for depression.
  • Each test used 8 mice in each group.
  • H-1 Depression Behavior Test H-1-1 Tail Suspension Test Mice were hung upside down from the tail for 6 minutes and the time of immobility was measured. The results are shown in FIG. The hung mouse moves around to escape. A longer immobility time indicates an increase in depressive behavior, and a shorter immobility time indicates a decrease.
  • the forced swimming test is a test using the fact that a mouse that has been forced to swim in an environment that cannot be avoided does not swim, and shows an increase in depressing behavior if the immobility time is long, and a decrease if it is short.
  • H-2 Spontaneous Activity Measurement At the same time as the above behavioral test for depression, spontaneous activity was measured for 10 minutes using a Supermex (Supermex, Muromachi Kikai Co., Ltd.) device.
  • FIG. 26 shows the result. There was no difference in the amount of spontaneous activity in any group. Therefore, it was confirmed that there was no difference in the amount of spontaneous activity between the depression model mice (LPS) and normal mice (Sal) subjected to the tail suspension test and the forced swimming test. It was also confirmed that the administration of silicon fine particles did not affect the amount of spontaneous activity.
  • the silicon fine particles in the present invention exhibit a high preventive effect and a high therapeutic effect against depression or depression.
  • the neurotoxin 6-hydroxydopamine hydrochloride (Sigma) (hereafter 6-OHDA) is suspended in physiological saline (Otsuka Pharmaceutical) containing 0.2% L (+)-ascorbic acid (Wako Pure Chemical Industries). A 2% 6-OHDA suspension was obtained.
  • the head of the mouse under anesthesia is fixed with a mouse-specific stereotaxic (Muromachi Kikai Co., Ltd.), and the left striatum (black matter-striatal tract: arrow portion in FIG.
  • One-sided Parkinson's disease model mice were divided into two groups: a silicon fine particle-containing group (6-OHDA + Si) and a normal group (6-OHDA) after the above operation.
  • normal mice that had not undergone surgery were divided into two groups: a silicon fine particle-containing diet group (Control + Si) and a normal diet group (Control).
  • Six mice and 6 mice in the normal food group (Control) group were used.
  • the degree of detachment of substantia nigra dopamine-producing cells was analyzed by a rotational movement test by administration of apomorphine and a fluorescent immunostaining method using an antibody against dopamine synthase (tyrosine hydroxylase), which is a dopamine-producing cell marker.
  • I-2 Rotational Exercise Test by Administration of Apomorphine Dopamine Receptor D1 / D2 Agonist
  • 1 mg / kg of apomorphine (SIGMA) diluted with physiological saline was intraperitoneally injected into each group of mice. The measurement was started 5 minutes after the administration, and the total number of rotations for 10 minutes was measured. The results are shown in FIG.
  • substantia nigra dopamine-producing cells are lost by 6-OHDA injection, dopamine in the striatum is depleted, and neurons with dopamine receptors in the striatum cause increased denervation sensitivity.
  • mice were perfusion-fixed with 4% paraformaldehyde fixative 5 weeks after the operation. Thereafter, the removed brain was frozen, and a frozen section having a thickness of 40 ⁇ m was prepared. At the time of section preparation, the injection site of 6-OHDA (left striatum) was confirmed by visual observation. The state of substantia nigra dopaminergic neurons was analyzed by fluorescent immunostaining using an antibody against tyrosine hydroxylase (dopaminergic cell marker). The degree of degeneration of the axons of the cell bodies and dendrites of the dopaminergic neurons in the substantia nigra and the production cells in the striatum was observed.
  • FIG. 29 shows the results of immunostaining of dopamine synthase (tyrosine hydroxylase) in the striatum.
  • dopamine synthase tyrosine hydroxylase
  • FIG. 30 shows the results of immunostaining of dopamine synthase (tyrosine hydroxylase) in the substantia nigra.
  • dopamine synthase tyrosine hydroxylase
  • I-4 Rotarod test In the rotarod test, a mouse is placed on a slowly rotating rod, and how long it stays on the gradually accelerating rod is observed. This is a test for evaluating sex. On the 4th week after the operation, the motor coordination of each group was measured by accelerating rotation with Muromachi Kikai Rotarod MK-610A MODE C. As shown in FIG. 31, in the normal diet group (6-OHDA) of Parkinson's disease model mice, the motor coordination was clearly reduced, whereas the silicon microparticle-containing diet group (6-OHDA + Si) of Parkinson's disease model mice. The motor coordination was comparable to that of the normal mouse group (Control + Si and Control). In Parkinson's disease model mice, the decrease in motor coordination was significantly suppressed by silicon microparticles.
  • I-5 Spontaneous activity measurement and open field test Spontaneous activity measurement and open field test were conducted 4 weeks after surgery.
  • the amount of spontaneous activity was measured for 10 minutes using Supermex (Supermex, Muromachi Kikai Co., Ltd.).
  • the open field test uses a square open field for mice (500mm x 500mm x 400mm) made by Muromachi Kikai Co., Ltd., and measured spontaneous activity (movement distance, movement speed, activity time / immobility time) in a novel environment. Measured for minutes.
  • FIG. 32 shows the result.
  • (A) is the spontaneous activity
  • (b) is the open field test travel distance
  • (c) is the open field test travel speed
  • (d) is the open field test activity time / immobility.
  • the silicon fine particles in the present invention exert a high preventive effect and a high therapeutic effect against Parkinson's disease.
  • FIG. 33 shows the results of measurement of ultrasonic vocal communication between mother and child.
  • the vertical axis in FIG. 33 represents the number of times the pup mouse uttered to the mother mouse.
  • the number of vocalizations was significantly reduced in the poly (I: C) administration group (B) of the normal diet.
  • the number of vocalizations was significantly recovered in the poly (I: C) administration group (D) of the silicon fine particle-containing food. From these results, it was clarified that the administration of the diet containing silicon fine particles restored social communication, and the effectiveness of the diet containing silicon fine particles was proved for the onset and symptoms of autism spectrum disorder.
  • the silicon fine particles in the present invention exert a high preventive effect and a high therapeutic effect against autism spectrum disease.
  • LPS lipopolysaccharide 1 mg / kg was intraperitoneally administered to produce a memory impairment model.
  • physiological saline (Sal) was intraperitoneally administered.
  • a context-conditioned fear memory test was performed on the 7th day (Day 7). Conditioning with electric shock was performed by placing the mouse in a chamber (Box) with electric wires on the floor and applying three electric shocks (0.6 mA, 2 seconds) (after entering the chamber 150 After one second, an electric shock was applied once from the sole, once after another 120 seconds, and once after another 120 seconds). The day after conditioning (24 hours later), the mice were placed in the conditioned chamber (Box) for 5 minutes, and the freezing time (seconds) of the mice was measured without applying an electric shock. The equipment used was a Fear Conditioning Box MK-450 (Muromachi Kikai). The results are shown in FIG. The vertical axis in FIG. 34 represents the ratio (%) of the freezing time in 5 minutes (300 seconds).
  • the normal diet mice administered LPS had a decreased freezing time and memory impairment was observed, whereas the mice fed the silicon microparticle-containing diet showed significant memory impairment. Was suppressed.
  • the test was performed using 9 mice in each group. At this time, the amount of spontaneous activity was measured for 10 minutes with Supermex (Muromachi Kikai) using 6 mice in each group, and there was no difference in the amount of spontaneous activity (FIG. 35).
  • the silicon fine particles in the present invention exhibit a high preventive effect and a high therapeutic effect against memory impairment.
  • a spinal cord injury model mouse was fed with a normal diet (Oriental Yeast Co., Ltd., model number AIN93M) and the above-mentioned diet containing silicon fine particles for one week before the injury surgery.
  • the motor function of each week up to 3 weeks after the operation was evaluated based on the following BBB (Basso, Beattie, and Bresnahan) scores.
  • the BBB score is severe if the score is low.
  • the score is 21 points (healthy) with the highest value, and the score is classified into 22 levels from 0 (complete hind limb paralysis) one by one.
  • the evaluation criteria in the values calculated as scores in FIGS. 36 and 37 are described.
  • BBB score 0 No movement of hind limb 1: Small movement of 1 hind limb and 1 joint 2: Large movement of 1 hind limb and small movement of 1 other joint 3: Large movement of 2 hind limbs 4: 3 hind limbs 5: Minor movement of 2 joints of the hind limb and large movement of the remaining 1 joint 6: Large movement of the 2 hind limb joints and minute movement of the remaining 1 joint
  • FIG. 36 shows the average values of the BBB scores of the normal diet group and the silicon fine particle-containing diet group in each week after the operation.
  • FIG. 37 shows the BBB scores of individual spinal cord injury model mice one week after the operation in terms of the number of mice with respect to the score.
  • the BBB score of the normal diet group was considerably low due to the influence of the spinal cord injury, whereas the score of the dietary group containing silicon fine particles was significantly high.
  • the BBB score of the normal food group was low, whereas the score of the silicon fine particle-containing food group tended to be high.
  • the decrease in motor function due to the effect of spinal cord injury was suppressed by silicon microparticles.
  • the silicon fine particles in the present invention exhibit a high preventive effect and a high therapeutic effect against spinal cord injury.
  • mice C57BL / 6J mice (male 7 weeks old) were obtained from Japan SLC. By exposing mice to noise, noise-induced hearing loss model mice were produced. The mice were fed with a normal diet (Oriental Yeast Co., Ltd., model number AIN93M) and the silicon fine particle-containing diet from 6 days before noise exposure to 7 days after exposure. The exposed noise condition is 116 dB of white noise for 4 hours. Auditory measurement before hearing noise, immediately after noise exposure, and 7 days after noise exposure (Auditory Brain-stem Response method: ABR method) The hearing of mice with normal diet was compared. Eight mice in each group were used. The results are shown in FIG.
  • ABR method Auditory Brain-stem Response method
  • the vertical axis represents the auditory threshold (dB), the horizontal axis represents the frequency (kHz), and the higher the auditory threshold, the lower the hearing ability.
  • dB auditory threshold
  • kHz frequency
  • the higher the auditory threshold the lower the hearing ability.
  • the silicon fine particles in the present invention exhibit a high preventive effect and a high therapeutic effect against hearing loss.
  • follow-up neuroological symptoms, survival rate
  • behavioral evaluation Elevated Body Swing test (modified)
  • N-1 Neurological symptoms
  • the neurological symptoms of the model rats during 90 minutes of ischemia were observed, and the following items were evaluated for each rat in four stages of 0 to 3. Severe neurological symptoms are severe (Modified Bederson method (Stroke Vol 17, No 3, 1986)).
  • the vertical axis of the graph in FIG. 39 is the average value of the evaluation points of each group. There was a tendency that neurological symptoms due to ischemia were alleviated by administration of silicon fine particles.
  • Forelimb paralysis When the rat's tail is lifted about 10 cm from the floor, the left forelimb is observed for bending. 0: No difference between left and right 1: There is difference 2: Flexion of about 90 ° 3: Unable to move left forelimb
  • Hind limb paralysis Observe the difference in undo force that occurs when the rat is pulled at hind limbs at rest. 0: No left / right difference 1: Muscle strength difference 2: Unnatural state is restored, but is restored by stimulation 3: Unnatural state, unresponsive to stimulation
  • Rotating motion Hold the rat's tail and exercise with the forelimbs on the floor.
  • FIG. 41 shows the ratio of swinging individuals among all evaluated individuals. Damage to the brain due to cerebral ischemia or reperfusion was greatly reduced by administration of silicon microparticles.
  • mice db / db mice male, 5 weeks old were obtained from Charles River, Japan.
  • the db / db mouse is a type 2 diabetes model showing a tendency to overeating because the leptin receptor involved in appetite control is deficient.
  • the mice were fed with a normal diet (Oriental Yeast Co., Ltd., model number AIN93M) and the above-mentioned diet containing silicon fine particles for 5 months to 3 months (17 weeks of age).
  • the weight measurement results are shown in FIG.
  • normal diet mice showed a significant increase in body weight due to the effect of overeating, whereas mice fed with a diet containing silicon fine particles significantly suppressed the increase.
  • mice ingesting a diet containing silicon fine particles showed a tendency to suppress the increase in blood glucose level, neutral fat level, total ketone body level and urine sugar level observed in diabetic patients.
  • diabetic model mice having 5 normal food groups and 5 silicon fine particle-containing food groups were used.
  • the silicon fine particles in the present invention exhibit a high preventive effect and a high therapeutic effect against diabetes.
  • a behavioral test (spontaneous activity measurement, rotarod test and open field test) was performed 20 hours after administration of the ethanol solution. In the spontaneous activity measurement and open field test, 10 mice were used in each group, and in the rotarod test, 12 mice were used in each group.
  • P-1 Measurement of spontaneous activity The spontaneous activity was measured for 10 minutes using Supermex (Supermex, Muromachi Kikai Co., Ltd.). As shown in FIG. 44, the spontaneous activity amount was decreased in the control group ( ⁇ ), while the decrease in the spontaneous activity amount was significantly suppressed in the silicon fine particle administration group ( ⁇ ).
  • P-2 Rotarod test In the rotarod test, place the mouse on a slowly rotating rod, observe how long it stays on the gradually accelerating rod, and coordinate the movement. This is a test for evaluating sex. Measured by Muromachi Kikai Rotor Rod MK-610A MODE C by accelerated rotation. As shown in FIG. 45, the motor coordination decreased in the control group ( ⁇ ), whereas the decrease in motor coordination was significantly suppressed in the silicon fine particle administration group ( ⁇ ).
  • FIG. 46 shows (a) moving distance, (b) moving speed, and (c) activity time / immobility time. As shown in FIG. 46, in the control group ( ⁇ ), the moving distance and moving speed decreased, whereas in the silicon fine particle administration group ( ⁇ ), the decrease in moving distance and moving speed was significantly suppressed.
  • the silicon fine particles in the present invention exert a high preventive effect and a high therapeutic effect against hangover.
  • the present invention can be one of the causal therapies for diseases caused by oxidative stress, and greatly contributes to future medical care and health promotion.

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Abstract

Le problème décrit par la présente invention concerne un médicament ou similaire qui peut prévenir ou traiter une maladie induite par le stress oxydatif. La solution selon l'invention porte sur un agent prophylactique ou thérapeutique contre une maladie induite par stress oxydatif, une composition pharmaceutique, un dispositif médical, un article d'hygiène, un aliment ou une boisson, qui contient des microparticules de silicium. Une maladie induite par le stress oxydatif peut être prévenue ou traitée par administration par voie orale de microparticules de silicium ou par placement de microparticules de silicium sur la peau ou une muqueuse. Des exemples de la maladie induite par le stress oxydatif comprennent une maladie inflammatoire et une dépression. Les microparticules de silicium possèdent un excellent effet prophylactique/thérapeutique.
PCT/JP2019/022558 2018-06-07 2019-06-06 Agent prophylactique ou thérapeutique contre une maladie induite par le stress oxydatif WO2019235577A1 (fr)

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CN201980038513.2A CN112351783A (zh) 2018-06-07 2019-06-06 氧化应激诱发的疾病的预防或治疗药物
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EP19815281.1A EP3804732B1 (fr) 2018-06-07 2019-06-06 Petites particules de silicone pour le traitement de maladies induites par le stress oxydatif
JP2019204864A JP7461003B2 (ja) 2018-11-13 2019-11-12 パーキンソン病の予防又は治療剤
JP2019210724A JP7461004B2 (ja) 2019-01-24 2019-11-21 記憶障害の予防又は治療剤
JP2019212972A JP7461006B2 (ja) 2019-01-24 2019-11-26 関節炎の予防又は治療剤
JP2019212974A JP7461008B2 (ja) 2019-01-24 2019-11-26 脊髄損傷後の障害もしくは症状の予防又は治療剤
JP2019213067A JP7461011B2 (ja) 2019-01-24 2019-11-26 難聴の予防又は治療剤
JP2019212971A JP7461005B2 (ja) 2019-01-24 2019-11-26 自閉スペクトラム症の予防又は治療剤
JP2019213066A JP7461010B2 (ja) 2019-06-06 2019-11-26 虚血性脳血管障害に伴う障害の予防又は治療剤
JP2019212973A JP7461007B2 (ja) 2019-01-24 2019-11-26 内臓不快感の予防又は治療剤
JP2019213065A JP7461009B2 (ja) 2019-01-24 2019-11-26 糖尿病の予防又は治療剤
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WO2021206020A1 (fr) * 2020-04-06 2021-10-14 国立大学法人大阪大学 Agent prophylactique ou thérapeutique contre le trouble de déficit de l'attention avec hyperactivité
WO2021215364A1 (fr) * 2020-04-23 2021-10-28 国立大学法人大阪大学 Agent de prévention ou de traitement d'une infection intra-utérine
WO2022259907A1 (fr) 2021-06-11 2022-12-15 国立大学法人大阪大学 Agent préventif ou thérapeutique contenant des particules fines de silicium pour des maladies

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WO2021199850A1 (fr) * 2020-04-02 2021-10-07 株式会社ボスケシリコン Inhibiteur de stress oxydatif et agent antioxydant
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WO2021206020A1 (fr) * 2020-04-06 2021-10-14 国立大学法人大阪大学 Agent prophylactique ou thérapeutique contre le trouble de déficit de l'attention avec hyperactivité
WO2021215364A1 (fr) * 2020-04-23 2021-10-28 国立大学法人大阪大学 Agent de prévention ou de traitement d'une infection intra-utérine
WO2022259907A1 (fr) 2021-06-11 2022-12-15 国立大学法人大阪大学 Agent préventif ou thérapeutique contenant des particules fines de silicium pour des maladies

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